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Cell Communication and Signaling : CCS Feb 2020Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients. To increase the breadth of patients that benefit from... (Review)
Review
Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients. To increase the breadth of patients that benefit from immunotherapy, new strategies that combat the immunosuppressive microenvironment of tumors are needed. Phosphatidylserine (PS) signaling is exploited by tumors to enhance tumor immune evasion and thus strategies to inhibit PS-mediated immune suppression have potential to increase the efficacy of immunotherapy. PS is a membrane lipid that flips to the outer surface of the cell membrane during apoptosis and/or cell stress. Externalized PS can drive efferocytosis or engage PS receptors (PSRs) to promote local immune suppression. In the tumor microenvironment (TME) PS-mediated immune suppression is often termed apoptotic mimicry. Monoclonal antibodies (mAbs) targeting PS or PSRs have been developed and are in preclinical and clinical testing. The TIM (T-cell/transmembrane, immunoglobulin, and mucin) and TAM (Tyro3, AXL, and MerTK) family of receptors are PSRs that have been shown to drive PS-mediated immune suppression in tumors. This review will highlight the development of mAbs targeting PS, TIM-3 and the TAM receptors. Video Abstract.
Topics: Animals; Antineoplastic Agents, Immunological; Humans; Immunotherapy; Neoplasms; Phosphatidylserines; Receptors, Cell Surface; Tumor Microenvironment
PubMed: 32087708
DOI: 10.1186/s12964-020-0521-5 -
Actas Espanolas de Psiquiatria Sep 2017Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and...
Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and non-pharmacological treatments are important fields of research at present. The Mediterranean diet (rich in fruits, vegetables, legumes, and olive oil, with regular fish consumption and low consumption of dairy products and meats) has been shown to reduce the incidence of mild cognitive impairment (MCI) and, probably, the conversion of MCI to dementia. Vitamins, especially vitamin E and the vitamins of the B group, have also been associated with the prevention of cognitive impairment due to their antioxidant effects. Ginkgo biloba is one of the most widely used supplements in the world for cognitive improvement because of its possible effects as a vasodilator and facilitator of cerebral vascularization. Green tea polyphenols have shown beneficial effects in different diseases, including cognitive impairment. Cerebral aging is associated with changes in the lipid composition of neuronal membranes, so it has been suggested that treatment with phospholipids like phosphatidylcholine and phosphatidylserine could favor cognitive improvement. Similarly, polyunsaturated and omega-3 fatty acids, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplements are associated with a beneficial effect on cognitive function due to the cumulative summation of factors that ultimately favor membrane permeability and neuronal functioning.
Topics: Cognitive Dysfunction; Dietary Supplements; Fatty Acids, Omega-3; Humans; Phosphatidylcholines; Phosphatidylserines; Vitamins
PubMed: 29171642
DOI: No ID Found -
Biochimica Et Biophysica Acta.... Apr 2023The ability of arginine-rich peptides to cross the lipid bilayer and enter cytoplasm, unlike their lysine-based analogues, is intensively studied in the context of...
Interaction of guanidinium and ammonium cations with phosphatidylcholine and phosphatidylserine lipid bilayers - Calorimetric, spectroscopic and molecular dynamics simulations study.
The ability of arginine-rich peptides to cross the lipid bilayer and enter cytoplasm, unlike their lysine-based analogues, is intensively studied in the context of cell-penetrating peptides. Although the experiments have not yet reconstructed their internalization mechanism, the computational studies have shown that the type or charge of lipid polar groups is one of the crucial factors in their translocation. In order to gain more detailed insight into the interaction of guanidinium (Gdm) and ammonium (NH) cations, as important building blocks in arginine and lysine amino acids, with lipid bilayers, we conducted the experimental and computational study that tackles this phenomenon. The adsorption of Gdm and NH on lipid bilayers prepared from a zwitterionic (DPPC) and an anionic (DPPS) lipid was examined by thermoanalytic and spectroscopic techniques. Using temperature-dependent UV-Vis spectroscopy and DSC calorimetry we determined the impact of Gdm and NH on the thermotropic properties of lipid bilayers. FTIR data, along with molecular dynamics simulations, unraveled the molecular-level details on the nature of their interactions, showing the proton transfer between NH and DPPS, but not between Gdm and DPPS. The findings originated from this work imply that Gdm and NH form qualitatively different interactions with lipids of different charge which is reflected in the physico-chemical interactions that arginine-and lysine-based peptides establish at a complex and chemically heterogeneous environment such as the biological membrane.
Topics: Lipid Bilayers; Phosphatidylserines; Guanidine; Molecular Dynamics Simulation; Lysine; Spectrum Analysis; Lecithins; Cell-Penetrating Peptides; Calorimetry; Arginine; Cations
PubMed: 36739930
DOI: 10.1016/j.bbamem.2023.184122 -
Surgery Nov 2019Phosphatidylserine is usually an intracellularly oriented cell membrane phospholipid. Externalized phosphatidylserine on activated cells is a signal for phagocytosis. In...
BACKGROUND
Phosphatidylserine is usually an intracellularly oriented cell membrane phospholipid. Externalized phosphatidylserine on activated cells is a signal for phagocytosis. In sepsis, persistent phosphatidylserine exposure is also a signal for activation of the coagulation and inflammatory cascades. As such, phosphatidylserine may be a key molecule in sepsis induced cellular and organ injury. We hypothesize that phosphatidylserine blockade provides a protective effect in sepsis induced organ dysfunction.
METHODS
Sepsis was induced in adult female rats using an endotoxin model. Diannexin, a homodimer of annexin A5, was administered for phosphatidylserine blockade. Rats were allocated to control (n = 5), sepsis (n = 6), or sepsis and phosphatidylserine blockade (n = 9) groups. Gut, pulmonary, renal, and hematologic dysfunctions were evaluated by mesenteric microvascular fluid leak, partial pressure of oxygen, serum creatinine, activated clotting time, and glomerular fibrin deposition, respectively.
RESULTS
Rats in the sepsis group demonstrated gut, renal, and hematologic dysfunction. Phosphatidylserine blockade reversed signs of gut dysfunction and mesenteric microvascular leak (P < .01). In addition, phosphatidylserine blockade corrected systemic coagulopathy, as measured by activated clotting time (P = .03) and glomerular fibrin deposition (P = .008). There was no difference in renal dysfunction (P = .1) or pulmonary dysfunction in any of the groups (P = .6).
CONCLUSION
In sepsis, phosphatidylserine blockade had a protective effect on gut dysfunction and coagulopathy. Increased phosphatidylserine exposure may be a key mediator of organ dysfunction and coagulopathy during sepsis. These data may provide insights into novel treatment options for septic patients.
Topics: Animals; Annexin A5; Disease Models, Animal; Female; Humans; Infusions, Intravenous; Lipopolysaccharides; Multiple Organ Failure; Phosphatidylserines; Rats; Sepsis; Treatment Outcome
PubMed: 31285044
DOI: 10.1016/j.surg.2019.05.020 -
Journal of Lipid Research Jun 2018This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and...
This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events. Moreover, mitochondrial function is severely impaired when the PE content of mitochondria is reduced below a threshold level. The discovery and implications of the existence of membrane contact sites between the endoplasmic reticulum and mitochondria and their relevance for PS and PE metabolism, as well as for mitochondrial function, are also discussed. Many of the recent advances in these fields are due to the use of isotope labeling for tracing biochemical pathways. In addition, techniques for disruption of specific genes in mice are now widely used and have provided major breakthroughs in understanding the roles and metabolism of PS and PE in vivo.
Topics: Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Mitochondria; Phosphatidylethanolamines; Phosphatidylserines
PubMed: 29661786
DOI: 10.1194/jlr.R084004 -
Molecules (Basel, Switzerland) Dec 2009In the 1970s, morphological evidence collected by electron microscopy linked mineral deposition ("calcification" or "mineralization") in newly-forming bone to... (Review)
Review
In the 1970s, morphological evidence collected by electron microscopy linked mineral deposition ("calcification" or "mineralization") in newly-forming bone to membrane-encapsulated particles of a diameter of approximately 100 nm (50-200 nm) that were called "matrix vesicles". As the characterisation of these vesicles progressed towards their biochemical composition, the role of lipids in the biomineralization process appeared to be crucial. In particular, a group of cell-membrane phospholipids were identified as major players in the crystal formation process. Indeed, in the 1980s it became clear that phosphatidylserine, together with proteins of the annexin family, was among the most important molecules in binding calcium ions and that this phospholipid was involved in the regulation of the early stages of mineralization in vivo. During the same period of time, the number of surgical implantations of orthopaedic, dental and maxilo-facial devices requiring full integration with the treated bone prompted the study of new functionalization molecules able to establish a stable bonding with the mineral phase of the host tissue. In the late 1990 s studies started that aimed at exploiting the potential of calcium-binding phospholipids and, in particular, of the phosphatidylserine as functionalization molecules to improve the osteointegration of artificial implants. Later, papers have been published that show the potential of the phophatidylserine and phosphatidylserine-mimicking coating technology to promote calcification both in vitro and in vivo. The promising results support the future clinical application of these novel osteointegrative biomaterials.
Topics: Animals; Bone Remodeling; Calcification, Physiologic; Microscopy, Electron; Models, Molecular; Phosphatidylserines; Rabbits
PubMed: 20032899
DOI: 10.3390/molecules14125367 -
International Journal of Molecular... Mar 2024As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of... (Review)
Review
As an important functional protein molecule in the human body, human annexin A5 (hAnxA5) is widely found in human cells and body fluids. hAnxA5, the smallest type of annexin, performs a variety of biological functions by reversibly and specifically binding phosphatidylserine (PS) in a calcium-dependent manner and plays an important role in many human physiological and pathological processes. The free state hAnxA5 exists in the form of monomers and usually forms a polymer in a specific self-assembly manner when exerting biological activity. This review systematically discusses the current knowledge and understanding of hAnxA5 from three perspectives: physiopathological relevance, diagnostic value, and therapeutic utility. AnxA5 affects the occurrence and development of many physiopathological processes. Moreover, hAnxA5 can be used independently or in combination as a biomarker of physiopathological phenomena for the diagnosis of certain diseases. Importantly, based on the properties of hAnxA5, many novel drug candidates have been designed and prepared for application in actual medical practice. However, there are also some gaps and shortcomings in AnxA5 research. This in-depth study will not only expand the understanding of structural and functional relationships but also promote the application of hAnxA5 in the field of biomedicine.
Topics: Humans; Annexin A5; Apoptosis; Calcium; Calcium, Dietary; Phosphatidylserines
PubMed: 38474114
DOI: 10.3390/ijms25052865 -
Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution.Traffic (Copenhagen, Denmark) Jan 2015It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then... (Review)
Review
It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then distributed to different cellular locations in order to create the distinct membrane compositions observed in eukaryotes. However, the mechanisms by which specific lipid species are trafficked to and maintained in specific areas of the cell are poorly understood and constitute an active area of research. Of particular interest is the distribution of phosphatidylserine (PS), an anionic lipid that is enriched in the cytosolic leaflet of the plasma membrane. PS transport occurs by both vesicular and non-vesicular routes, with members of the oxysterol-binding protein family (Osh6 and Osh7) recently implicated in the latter route. In addition, the flippase activity of P4-ATPases helps build PS membrane asymmetry by preferentially translocating PS to the cytosolic leaflet. This asymmetric PS distribution can be used as a signaling device by the regulated activation of scramblases, which rapidly expose PS on the extracellular leaflet and play important roles in blood clotting and apoptosis. This review will discuss recent advances made in the study of phospholipid flippases, scramblases and PS-specific lipid transfer proteins, as well as how these proteins contribute to subcellular PS distribution.
Topics: Adenosine Triphosphatases; Animals; Biological Transport; Cell Membrane; Endoplasmic Reticulum; Humans; Phosphatidylserines; Phospholipids
PubMed: 25284293
DOI: 10.1111/tra.12233 -
Cell Communication and Signaling : CCS Jan 2020Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of... (Review)
Review
Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of cancer cells. This has allowed for the development of selective therapeutic agents against cancer cells (without affecting healthy cells). SapC-DOPS is a PS-targeting nanovesicle which effectively targets and kills several cancer types including pancreatic, lung, brain, and pediatric tumors. Our studies have demonstrated that SapC-DOPS selectively induces apoptotic cell death in malignant and metastatic cells, whereas untransformed cells remain unaffected due to low surface PS expression. Furthermore, SapC-DOPS can be used in combination with standard therapies such as irradiation and chemotherapeutic drugs to significantly enhance the antitumor efficacy of these treatments. While the PS-targeting nanovesicles are a promising selective therapeutic option for the treatment of cancers, more preclinical studies are needed to fully understand the mechanisms leading to non-apoptotic PS expression on the surface of viable cancer cells and to determine the effectiveness of SapC-DOPS in advanced metastatic disease. In addition, the completion of clinical studies will determine therapeutic effects and drug safety in patients. A phase I clinical trial using SapC-DOPS has been completed on patients with solid tumors and has demonstrated compelling patient outcomes with a strong safety profile. Results from this study are informing future studies with SapC-DOPS. Abstract video.
Topics: Animals; Clinical Trials as Topic; Humans; Nanoparticles; Neoplasms; Phosphatidylserines; Saposins
PubMed: 31918715
DOI: 10.1186/s12964-019-0476-6 -
IUBMB Life Mar 2022Indole propionic acid (IPA) which majorly influences the modulation of cellular respiration is a metabolite generated by gut microbiota. The antimicrobial effects of IPA...
Indole propionic acid (IPA) which majorly influences the modulation of cellular respiration is a metabolite generated by gut microbiota. The antimicrobial effects of IPA have not been previously demonstrated. Therefore, this study focused on investigating the antimicrobial activity of IPA. Initially, antifungal activity of IPA against Candida albicans was observed, accompanied by variations in mitochondrial respiration indicating modulation of NAD /NADH ratios. Consumption of O contributes to the respiratory regulation and triggered by Ca overloading. After treatment with IPA, the cells were monitored, and Ca increases leading to membrane depolarization and reactive oxygen species (ROS) accumulation in mitochondria were noted. Depolarization of mitochondria membrane induced release of proapoptotic proteins in mitochondria. Oxidative stress exerted by ROS contributed to glutathione depletion and oxidation of glutathione (GSH). Fragmentation of DNA is a characteristic event leading to apoptosis and accompanies major hallmarks of apoptosis including phosphatidylserine exposure and metacaspase activation. In addition, phosphatidylserine exposure and metacaspase activation were detected in the cell treated with IPA. In conclusion, IPA triggered apoptosis in C. albicans under the influence of Ca .
Topics: Antifungal Agents; Apoptosis; Candida albicans; Glutathione; Indoles; Membrane Potential, Mitochondrial; Phosphatidylserines; Propionates; Reactive Oxygen Species
PubMed: 34779568
DOI: 10.1002/iub.2579